Of the average 57 million annual deaths over the past ten years, more than 20 million are directly due to infectious diseases with millions more due to secondary effects of infections. The numbers of annual deaths due to infections by Salmonella Typhi, Streptococcus pneumoniae and Mycobacterium tuberculosis (Mtb) vary widely but may account for about 13 per cent of the total deaths with an even greater cost due to the severe morbidity associated with these diseases. In the belief that improving health, nutrition and economic well being (the latter dependent on the first two) provide the best means to enhance the quality of life globally, we propose a vaccine development program based on our recent technical developments in using recombinant attenuated Salmonella vaccines (RASV). Our Specific Aims are: (1) to evaluate S. Typhimurium RASVs with recently perfected and improved genotypes to deliver five different S. pneumoniae protective protein antigens and compare antigen delivery by a mixture of three strains versus a single strain delivering all five antigens o maximize induction of mucosal and systemic antibody responses and to evaluate (i) antibody affinity to a diversity of S. pneumoniae strains representing the major serotypes distributed globally and (ii) induction of protective immunity to intranasal colonization and lethal challenge with mouse-adapted S. pneumoniae strains, (2) to conduct all needed preclinical studies with the optimal S. Typhimurium RASV and with the S. Typhi RASV of essentially the same genotype to validate the S. Typhi RASV for evaluation in future human clinical trials and to then support such clinical trials by providing strains and reagents and assisting in evaluations and verifications, as necessary, (3) to perfect the improved RASV regulated delayed lysis system for delivery of Mtb antigens by T2SS, T3SS and lysis in eukaryotic cell cytosol to generate both CD4- and CD8-dependent immunities against Mtb infection and to evaluate protection conferred by immunization by RASV-Mtb vaccines alone and following initial immunization with M. bovis BCG, and (4) to design, construct and evaluate recombinant attenuated S. Typhi regulated delayed lysis systems producing the optimal combination of Mtb antigens (determined from Specific Aim 3 and delivered by T2SS, T3SS and lysis in the eukaryotic cell cytosol to confer protection against Mtb infection. We will add to our Master File (filed with FDA), prepare and fully characterize candidate vaccine Master Seeds for stability and safety, prepare and submit protocols for IRB approvals, submit information necessary to obtain INDs, and perform any other work needed to arrange that the best candidate vaccines be clinically evaluated in future studies.